3,3-diphenylpropylamines are known which act as muscarinic receptor antagonists and are useful in the treatment of urinary incontinence and other symptoms of urinary bladder hyperactivity. Said compounds include the compound N,N-diisopropyl-3-(2-hydroxy-5-methylphenyl)-3-phenylpropylamine, the (R) enantiomer of which is tolterodine, the International Nonproprietary Name of the compound (R)-(+)-N,N-diisopropyl-3-(2-hydroxy-5-methylphenyl)-3-phenylpropylamine [(R)-tolterodine]. The (S) enantiomer, (S)-(−)-N,N-diisopropyl-3-(2-hydroxy-5-methylphenyl)-3-phenylpropylamine or (S)-tolterodine, and its use in the treatment of urinary and gastrointestinal disorders has been described in international patent application WO 98/03067. The use of tolterodine and some of its derivatives in the treatment of asthma in mammals has been described in U.S. Pat. No. 6,538,035.
Tolterodine and other 3,3-diphenylpropylamines analogs were first described in U.S. Pat. No. 5,382,600. Said patent described several methods for preparing tolterodine and its analogs generally based on displacing a tosylate with diisopropylamine. Said method has several drawbacks. The displacement reaction occurs very slowly, therefore several days are needed to carry out said reaction, and the total yields are low. Some of the reagents used such as methyl iodide or lithium aluminium hydride are expensive and their use involves a hazard. All this makes the total method expensive and not very productive.
An alternative method of obtaining tolterodine is described in U.S. Pat. No. 5,922,914. Said method comprises reducing 3,4-dihydro-6-methyl-4-phenyl-2H-benzopyran-2-one with DIBAL (diisobutylaluminum hydride) in toluene to give the corresponding hemiketal 6-methyl-4-phenyl-3,4-dihydro-2H-1-benzopyran-2-ol which is then subjected to reductive amination to yield racemic tolterodine. This method also has some drawbacks because the DIBAL reagent is used, which is expensive and hazardous, therefore it is not suitable for being put into practice on an industrial level.
International patent application WO 03/014060 describes a method of obtaining tolterodine which, although it partially solves some drawbacks of the previous methods, still includes problematic steps, particularly obtaining the intermediate 3-(2-methoxy-5-methylphenyl)-3-phenylpropanol, transforming it into the tosylate derivative and subsequently displacing the tosylate with diisopropylamine. These steps still have serious problems, such as the steric hindrance of diisopropylamine in the tosylate displacement reaction, making the nucleophilic substitution reaction difficult, the high temperatures necessary for it, as well as the long reaction times that they comprise, even days.
A different approach for preparing the (R)-tolterodine enantiomer is formed by several enantioselective syntheses such as those described in U.S. Pat. No. 6,310,248 or by Andersson et al. in J. Org. Chem. 1998, 63, 8067-8070, describing methods in which the participation of asymmetry inducers or chiral auxiliaries respectively, which are generally very expensive reagents, is necessary.
An alternative method to tolterodine synthesis which allows reducing the cost of the method and at the same time achieves good yields and the use of less hazardous reagents is described in Spanish patent application ES 2,235,648. This document details obtaining tolterodine by means of a synthetic route comprising a reductive amination reaction between a 3,3-diphenylpropanal derivative and diisopropylamine in the presence of a reducing agent. Nevertheless, obtaining the starting aldehyde requires several synthetic steps considerably lengthening the global method.
It is therefore necessary to solve the problems associated with the methods belonging to the state of the art and to provide an alternative method of obtaining tolterodine and other 3,3-diphenylpropylamines analogs which improves the cost-effectiveness of the process by using more cost-effective reagents and starting materials which further allow reducing the number of steps of the synthetic route leading to obtaining it. Said method must advantageously be applicable on an industrial level and must provide the desired product with a good yield and quality.